The biotransformation of gamma-aminobutyric acid (GABA) to succinic acid semialdehyde, which is catalyzed by the enzyme GABA-transaminase (GABA-T), is the primary reaction responsible for the catabolism of GABA, an inhibitory neurotransmitter of the central nervous system. It is known that low levels of endogenous GABA are associated with seizure disorders (such as those involved in epilepsy, alcohol withdrawal, or barbiturate withdrawal), with disorders involving involuntary movement (such as those caused by the extrapyrimidal effects of drugs, for example tardive dyskinesia, with certain psychiatric disorders (such as schizophrenia and depression) and with muscle spasticity. Blockade of the transformation of GABA to succinic acid semialdehyde, such as by irreversible inhibition of GABA-T, can elevate GABA levels in the central nervous system (CNS) and, thus provides a means for treating the disorders of the central nervous system associated with low GABA levels.
Certain compounds are known to be irreversible inhibitors of GABA-T and thereby to elevate brain levels of GABA. Examples are 4-aminohex-5-enoic acid ("vinyl GABA") and 4-aminohex-5-ynoic acid ("acetylenic GABA") [See U.S. Pat. Nos. 3,960,927 and 3,959,356; Lippert et al., Eur. J. Biochem., 74, 441 (1977); Lippert et al., Brain Research Bulletin, 5, Suppl. 2, 375 (1980); Jung et al., Journal of Neurochemistry, 28 717 (1977); Palfreyman et al., GABA-Neuro-transmitter, Alfred Benzon Symposium 12; Larsen et al., Editors, Munksgaard, Copenhagen, 1979, pages 432-446; Jung et al., Biochemical and Biophysical Research Communications, 67, 301 (1975); and Palfreyman et al., Biochemical Pharmacology, 30, 817 (1981]. A further example is 1-acetylene-1,4-butanediamine ("acetylenic putrescine") (see U.S. Pat. No. 4,139,563)